The enzyme targeted by a new class of experimental antimalarial
drugs has been identified, raising hope of a treatment that can
cure, prevent and block transmission of the disease.
The enzyme is vital for the growth and development of multiple
species of the Plasmodium parasites that cause malaria and is
required at all stages in the parasite life cycle. It is the first
pre-clinically validated drug target that is active at all stages
in the parasite life cycle, laying the foundations for the
development of next-generation antimalarial drugs.
To eliminate malaria, medicines need to be effective against the
dormant liver-stage infection that can cause relapses, as well as
the symptomatic blood stage, and should also block transmission of
the parasite to mosquitoes that spread the disease.
The imidazopyrazines are a new class of experimental
antimalarial drugs that are being developed by scientists at
Novartis with support from the Wellcome Trust and the Medicines for
Malaria Venture. They have potent preventive, therapeutic and
transmission-blocking activity in animal models of malaria and are
also effective against two species of malaria parasite taken from
patient samples. However, until now, the target of this class of
experimental drugs was not known.
To investigate this, the international team created parasite
strains in the laboratory that are resistant to treatment with the
imidazopyrazines and then used genetic sequencing to identify the
genes that are mutated to confer resistance. In all cases, the
mutation occurred in the gene for PI4K, an enzyme involved in fatty
acid metabolism that is active across all stages in the parasite
life cycle.
Thierry Diagana, Head of the Novartis Institute for Tropical
Diseases, said: "This new target for malaria provides an avenue to
develop the next-generation antimalarial drugs that are capable of
preventing, treating and blocking the spread of malaria."
Dr Richard Seabrook, Head of Business Development at the
Wellcome Trust, said: "With growing resistance to existing
therapies, we urgently need new malaria medicines to combat the
spread of this deadly disease. This discovery is particularly
exciting as it identifies a druggable target that is effective in
multiple species of the malaria parasite and at all stages of the
parasite life cycle, features that are considered vital for a
treatment capable of eliminating malaria."
The imidazopyrazine compounds used in this study may serve
primarily as tools for understanding more about the biology of the
malaria life cycle; however, the authors suggest that further
optimisation could lead to clinical candidates with desirable
drug-like characteristics.
The paper, Targeting Plasmodium PI(4)K to eliminate malaria, is published
in Nature.